Patients with chronic type B hepatitis are being evaluated and followed prospectively to determine the long-term natural history of this common form of chronic liver disease. Selected patients have been entered into therapeutic trials of antiviral or immunomodulatory agents. Several agents have been evaluated including alpha interferon, ribavirin, and fluoro-iodo arabinofuranosyl-uracil (FIAU). Alpha interferon continues to be evaluated in atypical or unusual patients who would ordinarily be excluded from controlled trials including those with decompensated cirrhosis, extra- hepatic complications of hepatitis B, atypical serologic markers and children with hepatitis B. A pilot study of ribavirin in 18 patients with chronic hepatitis B found that both serum HBV DNA and alanine aminotransferase (ALT) levels decreased significantly within 4 weeks of starting therapy. The decrease in mean HBV DNA averaged 23%. Mean ALT levels decreased by 40%, becoming normal in 4 patients at the end of treatment. However, these changes were transient only. Only 1 patient lost hepatitis B e antigen from serum during therapy. Subsequently, HBeAG reappeared and HBV DNA again became detectable in this individual. A pilot study of FIAU, a nucleoside analogue, is currently underway. Nine patients have completed 4 weeks of therapy and have been followed for at least 1 week after stopping FIAU. At all doses of FIAU tested so far (0.05, 0.1 and 0.25 mg/kg/day), therapy is associated with marked suppression (85% decrease) of serum HBV DNA levels after 4 weeks of therapy. FIAU appears to be well-tolerated with few side effects.